PROJECT SUMMARY Aberrant glial activation has been postulated to promote neurodegeneration. But, what triggers glial activation and how perturbations to glia-neuron interaction contribute to brain aging and neurodegeneration remains unclear. The scientific premise of this proposal is based on previously published work that dominant mutation in human Progranulin (GRN) gene is a major cause for frontotemporal dementia (FTD). Mutations in GRN cause a drastic reduction in Progranulin (PGRN) protein levels in brain tissues and eventually lead to neuropathology characterized by profound gliosis, severe neuron loss, and aggregation of RNA binding protein TDP-43 in remaining neurons (also known as ?TDP-43 proteinopathy?). In addition to its role in FTD, single nucleotide polymorphism (SNP) in the GRN gene has been associated with increased risk of TDP-43 proteinopathy in Alzheimer's disease (AD) and in the aging brain. Together, these results support the idea that PGRN deficiency may have broader impacts on neurodegeneration. To investigate the role of PGRN deficiency in neurodegeneration, we have shown that mouse models of PGRN deficiency recapitulate several key neuropathological features in FTD caused by GRN mutations, including microglial activation, microglia-mediated synaptic pruning, and dysfunction in the thalamocortical circuit, which contribute to obsessive-compulsive disorder (OCD)-like behaviors in these mice. In addition, we used single cell transcriptomic analyses to show that Grn-/- microglia exhibit early onset and persistent transcriptomic changes in genes involved in the endolysosomal pathway and innate immunity functions. Furthermore, proteomic and morphological analyses in Grn-/- microglia revealed prominent features of cellular senescence, including increased phagocytosis, lysosomal dysfunction, proliferative arrest, and increased secretion of complements C1q and C3b. These results support the hypothesis that PGRN deficiency disrupts endolysosomal function and activates the cellular senescence program in microglia leading to persistent microglial activation to promote synaptic pruning and neuronal cell death. To test this hypothesis, we will (1) determine the role of integrin ?v?3 and TGF-? pathway in promoting cellular senescence in Grn-/- microglia, (2) characterize the secretory phenotype in senescent microglia in Grn-/- mice and its impact on neurodegeneration, and (3) elucidate the impact of PGRN deficiency on microglial senescence and neurodegeneration in FTD and Alzheimer's disease. Results from this proposal will provide critical insights into the mechanism of PGRN deficiency in microglial senescence and its role in neurodegeneration in FTD and AD.